Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction

ABSTRACT

The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+  activated potassium channel (IK Ca ), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction.

TECHNICAL FIELD

[0001] The present invention relates to chemical compounds havinginhibitory activity on an intermediate conductance Ca²⁺ activatedpotassium channel (IK_(Ca)), and the use of such compounds for thetreatment or alleviation of diseases or conditions relating to immunedysfunction.

BACKGROUND ART

[0002] Ion channels are transmembrane proteins, which catalyse thetransport of inorganic ions across cell membranes. The ion channelsparticipate in processes as diverse as the generation and timing ofaction potentials, synaptic transmissions, secretion of hormones,contraction of muscles, etc.

[0003] Many drugs exert their effects via modulation of ion channels.Examples are anti-epileptic compounds like Phenytoin and Lamotrigine,which block voltage dependent Na⁺-channels in the brain,anti-hypertensive drugs like Nifedipine and Diltiazem, which blockvoltage dependent Ca²⁺-channels in smooth muscle cells, and stimulatorsof insulin release like Glibenclamide and Tolbutamide, which block anATP-regulated K⁺-channel in the pancreas.

[0004] There is a large and still growing demand for non-toxicimmune-regulating agents for use in relation to e.g. organtransplantation and auto-immune diseases.

[0005] Some of the currently used immune-suppressive compounds such asCyclosporin A and FK506 prevent immunological proliferation byinhibition of the Ca²⁺/calmodulin-dependent Ser/Thr phosphatasecalcineurin. The usefulness of this class of compounds is limited bytheir side effects such as renal dysfunction, arterial hypertension,neurological effects (headache, insomnia, tremors, parasthesias,lethargy), gastrointestinal effects (nausea, vomiting, diarrhoea), anddiabetes.

[0006] Another class of compounds comprising e.g. Azathioprine andMizorbine interfere in a cytotoxic manner directly with theDNA-replication process. Although cytotoxicity shows some selectivitytowards strongly proliferating cells such as activated T- andB-lymphocytes, complications may follow due to effects on dividing cellsin the entire body, including bone marrow, hair sacs, the skin, testis,ovary and epithelia such as the airways, the intestinal tract, and thethick ascending limp of the loop of Henle's.

[0007] A fairly new approach for suppression of immune responses is tointerfere with ion channels in the plasma membrane of cells in theimmune system, especially the T- and B-lymphocytes. Upon exposure toantigens by antigen presenting macrophages or to mitogens such as IL-2or IFN-γ, an initial signal in the switching from the resting phase tothe proliferating phase is an activation of the phosphoinositidesignalling pathway resulting in an increase in the intracellularconcentration of Ca²⁺ ([Ca²⁺]₁) due to Ca²⁺ release from intracellularstores. A sustained elevated [Ca²⁺]₁ is maintained by an increasedpassive influx through mitogen regulated, voltage-independentCa-channels. This increase in [Ca²⁺]₁, is vital for the subsequentevents leading to cell proliferation and secretion of lymphokines.

[0008] In resting T- and B-lymphocytes, the [Ca²⁺] is approximately 10⁷fold higher outside versus inside the cell, and the membrane potentialis negative inside, i.e. there is an inwardly directed electrochemicalCa²⁺ gradient. Thus, when the Ca-channels are activated they conduct Cainto the cell. However, Ca²⁺ influx via the Ca-channels, tends to reduceor even eliminate this gradient, and thus to reduce the influx.Concomitant opening of K-channels keeps the membrane potential negative,and activation of these channels is therefore essential for maintaininga large inwardly directed, electrochemical driving force for Ca²⁺.

[0009] In the presence of blockers of lymphocyte K-channels, the cellsdepolarise, and thereby the Ca²⁺ influx necessary for the activation ofthe immune response is reduced.

[0010] Several types of K-channels have been described in B- andT-lymphocytes including both voltage-dependent K-channels (K_(v)), andvoltage-independent Ca²⁺-activated K-channels (K_(Ca)). It is wellestablished, that the K_(v)-channels are activated by the Ca²⁺-induceddepolarisation of the lymphocyte, and non-selective blockers ofK_(v)-channels are therefore quite effective immune-suppressive agents.However, these compounds in general have severe side effects due toblock of re polarization in excitable tissue (seizures, myotonic runs,high blood pressure, etc.).

[0011] Considerable effort has been made into the development ofimmune-selective K_(V)-blockers. The molecular rationale for this, hasbeen the observation that T-lymphocytes express homomericK_(V)1.3-channels in contrast to excitable cells, which always expressseveral heteromeric subtypes of the K_(v)-channels.

[0012] A selective blocker of the K_(V)1.3-homomer might therefore be anideal, relatively non-toxic, immune-suppressive agent. Initial reportsfrom these pharmacological programs indicate that selectiveK_(V)1.3-blockers are very effective as anti-inflammatory agents.However, the well-known toxicity of non-selective K_(V)-blockers hasapparently not disappeared. An example is the potent K_(v)1.3 blockerCP-339,818. This compound is also a potent blocker of K_(v)1.4, acardiac and neuronal A-type K-channel. The side-effect of this compoundis predicted to be interference with the cardiac action potential (longQT-syndrome toxicity) as well as with the action potentialrepolarization and after hyperpolarization in neurons.

[0013] WO 97/34589 describes triaryl methane compounds that inhibitmammalian cell proliferation, inhibit the Gardos channel oferythrocytes, reduce sickle erythrocyte dehydration and/or delay theoccurrence of erythrocyte sickling or deformation, and suggest the useof these compounds in abnormal cell proliferation. However, the effectof these compounds on human T cell proliferation, the use of suchcompounds in normal cell proliferation as immune-suppressive agents, aswell as their unexpected properties when used in combination therapy hasnever been disclosed.

SUMMARY OF THE INVENTION

[0014] A hitherto untested alternative to the block of thevoltage-dependent K-channels is a selective inhibition of theCa²⁺-activated K-channels in T- and B-lymphocytes. These channels aredirectly activated by the increased [Ca²⁺]₁ which is the primary signalfor lymphocyte activation. Further, contrary to K_(V)-channels, thesechannels are voltage-independent, and therefore they do not close uponhyperpolarization, implicating that they are even more effective thanK_(v) channels in maintaining a large inward driving force on Ca²⁺ underconditions of elevated intercellular Ca²⁺-concentrations.

[0015] Two types of Ca²⁺-activated K-channels have been described fromlymphocytes: 1) Small-conductance, apamin-sensitive, Ca²⁺-activatedK-channels (SK_(Ca)) and 2) Intermediate-conductance, inwardlyrectifying, Clotrimazole-sensitive, Ca²⁺-activated K-channels (IK_(Ca)),also referred to as Gardos-channels. Resting T-lymphocytes express bothSK_(Ca) and IK_(Ca), whereas B-lymphocytes only express IK_(Ca).

[0016] Upon activation, prior to cell proliferation, the expressionlevel of IK_(Ca) increases approximately 30 fold in both T- andB-lymphocytes. The expression levels of both K_(V)1.3 and SK_(Ca) remainunchanged, indicating a major role for the IK_(Ca)-channel in inductionof T- and B-cell proliferation. Contrary to the SK_(Ca)-channels, whichare extensively expressed in CNS and heart (measured as mRNA abundanceby Northern hybridisation) and in PNS, skeletal muscle, hepatocytes(measured as functional channels by electrophysiology), expression ofIK_(Ca)-channels have never been reported from any excitable tissue. Infact, blood cells such as erythrocytes, monocytes, lymphocytes,endothelial cells, and certain cell-lines with an epithelial ancestry,Ehrlich ascites tumour cells and HeLa cells appear to be the main sourceof this type of channels.

[0017] Furthermore, the very recent cloning of IK_(Ca) has enabled thedemonstration of the mRNA for this gene in several organs includingplacenta, salivary glands, lung and pancreas. Thus, specific blockers ofIK_(Ca) are likely to be very effective as immune-suppressive agents,and devoid of side effects on excitable tissue. In fact, theIK_(Ca)-inhibitor Clotrimazole (which is also a blocker of thecytochrome P-450 system) has been extensively used clinically in thesystemic treatment of fungal infections. No toxicity related toK-channel blockade has been described.

[0018] Accordingly, in its first aspect, the invention relates to theuse of a chemical compound having IK_(Ca) inhibitory activity for themanufacture of a medicament for the treatment or alleviation ofdiseases, disorders or conditions relating to immune dysfunction.

[0019] In another aspect the invention provides a pharmaceuticalcompositions for use in the treatment or alleviation of diseases,disorders or conditions relating to immune dysfunction, comprising aneffective amount of a chemical compound having IK_(Ca) inhibitoryactivity.

DETAILED DISCLOSURE OF THE INVENTION

[0020] The present invention relates to the use of a chemical compoundhaving selective IK_(Ca) inhibitory activity for treatment oralleviation of diseases or conditions relating to immune dysfunction.

[0021] Chemical Compound Having IK_(Ca) Inhibitory Activity

[0022] According to the invention, chemical compounds having selectiveIK_(Ca) inhibitory activity may be identified by its ability to inhibitcurrent through an IK_(Ca) channel, while showing essentially no effectat other potassium channels at a 10 fold higher concentration, asdetermined by conventional patch clamp technique.

[0023] The compounds for use according to the invention show IK_(Ca)inhibitory activity in concentrations below 100 μM, preferably below 10μM, more preferred below 1 μm. In its most preferred embodimentcompounds show IK_(Ca) inhibitory activity show activity in lowmicromolar and the nanomolar range.

[0024] In a preferred embodiment the chemical compounds for useaccording to the invention showing selective IK_(Ca) inhibitory activityare triaryl methane derivatives represented by the general Formula I

[0025] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0026] wherein,

[0027] n is 0, 1, 2, 3, 4, 5 or 6;

[0028] X is absent, or represent a group of the formula —(CH₂)_(n)—, ofthe formula —(CH₂)_(n)—Z— (in either direction), of the formula—(CH₂)_(n)—CH═N— (in either direction), the formula—(CH₂)_(n)—Z—(CH₂)_(m)—, or of the formula —(CH₂)_(n)—CH═N—(CH₂)_(m)—(in either direction), or a group of the formula —R′″C(O)N—;

[0029] in which formulas n and m, independently of each another,represent 0, 1, 2, 3 or 4; and Z represents O, S, or NR′″, wherein R′″represents hydrogen or alkyl;

[0030] Y represents a carbon atom (C), a nitrogen atom (N), or aphosphor atom (P), a silicium atom (Si), or a germanium atom (Ge);

[0031] Ar¹, Ar² and Ar³, independently of each another, represents apartially or completely saturated mono- or polycyclic aryl group, or amono- or poly-heterocyclic group, which mono- or polycyclic groups mayoptionally be substituted one or more times with substituents selectedfrom the group consisting of halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR″, —SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″,—C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″),—C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂,—CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂,—CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″;

[0032] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; and

[0033] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0034] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaI wherein;

[0035] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0036] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0037] In another preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaII

[0038] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0039] wherein,

[0040] n is 0, 1, 2, 3, 4, 5 or 6;

[0041] Ar¹ represents a partially or completely saturated mono- orpolycyclic aryl is group, or a mono- or poly-heterocyclic group, whichmono- or polycyclic groups may optionally be substituted one or moretimes with substituents selected from the group consisting of halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR″, —SR″, —R′OR″, —R′SR″, —C(O)R″,—C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″),—C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂,—C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂,—CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″;

[0042] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0043] which triaryl methane derivative may further be substituted oneor more times with a substituent X selected from the group consisting ofhydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR″, —SR″,—R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0044] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaII wherein;

[0045] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0046] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0047] In a third preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaIII

[0048] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0049] wherein,

[0050] n is 0, 1, 2, 3, 4, 5, or 6;

[0051] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0052] R¹, R², R³ and R⁴, independently of each another, representshydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR″, —SR″,—R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and

[0053] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0054] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaIII wherein

[0055] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0056] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0057] In a fourth preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaIV

[0058] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0059] wherein,

[0060] n is 0, 1, 2, 3, 4, 5, or 6;

[0061] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0062] R¹, R² and R³, independently of each another, representshydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR″, —SR″,—R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and

[0063] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0064] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaIV wherein the partially or completely saturated mono- or polycyclicaryl group is selected from the group consisting phenyl, biphenyl,naphthyl, or cyclopenta-2,4-diene-1-ylidene; and

[0065] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0066] In a fifth preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaV

[0067] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0068] wherein,

[0069] n is 0, 1, 2, 3, 4, 5, or 6;

[0070] Ar¹ represents a partially or completely saturated mono- orpolycyclic aryl group, or a mono- or poly-heterocyclic group, whichmono- or polycyclic groups may optionally be substituted one or moretimes with substituents selected from the group consisting of hydrogen,halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino,nitro or cyano, or a group of the formula —OR″, —SR″, —R′OR″, —R′SR″,—C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″),—C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂,—C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂,—CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″;

[0071] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0072] R¹ and R², independently of each another, represents hydrogen,halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino,nitro or cyano, or a group of the formula —OR″, —SR″, —R′OR″, —R′SR″,—C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″),—C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂,—C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂,—CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″; and

[0073] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0074] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaV wherein;

[0075] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0076] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0077] In a sixth preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaVI

[0078] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0079] wherein,

[0080] n is 0, 1, 2, 3, 4, 5, or 6;

[0081] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0082] R¹, R², R³ and R⁴, independently of each another, representshydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR″, —SR″,—R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and

[0083] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0084] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaVI wherein;

[0085] the partially or completely saturated mono- or polycyclic arylgroup is elected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0086] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0087] In a seventh preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaVII

[0088] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0089] wherein,

[0090] n is 0, 1, 2, 3, 4, 5, or 6;

[0091] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0092] R¹, R² and R³, independently of each another, representshydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR″, —SR″,—R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and

[0093] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0094] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaVII wherein;

[0095] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0096] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0097] In an eight preferred embodiment the triaryl methane derivativefor use according to the invention is represented by the general FormulaVIII

[0098] and a pharmaceutically acceptable salt or an oxide or a hydratethereof,

[0099] wherein,

[0100] n is 0, 1, 2, 3, 4, 5, or 6;

[0101] Ar¹ represents a partially or completely saturated mono- orpolycyclic aryl group, or a mono- or poly-heterocyclic group, whichmono- or polycyclic groups may optionally be substituted one or moretimes with substituents selected from the group consisting of hydrogen,halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino,nitro or cyano, or a group of the formula —OR″, —SR″, —R′OR″, —R′SR″,—C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″),—C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂,—C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂,—CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″;

[0102] R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′;

[0103] R′ and R″, independently of each another, represents hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.

[0104] In a more preferred embodiment, the triaryl methane derivativefor use according to the invention is represented by the general FormulaVIII wherein;

[0105] the partially or completely saturated mono- or polycyclic arylgroup is selected from the group consisting phenyl, biphenyl, naphthyl,or cyclopenta-2,4-diene-1-ylidene; and

[0106] the mono- or poly-heterocyclic group is A 5- and 6 memberedheterocyclic monocyclic group selected from the group consisting offuranyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.

[0107] Definition of Substituents

[0108] In the context of this invention halogen represents a fluorine, achlorine, a bromine or a iodine atom. Thus, a trihalogenmethyl grouprepresents e.g. a trifluoromethyl group and a trichloromethyl group.

[0109] In the context of this invention an alkyl group designates aunivalent saturated, straight or branched hydrocarbon chain. Thehydrocarbon chain preferably contain of from one to eighteen carbonatoms (C₁₋₁₈-alkyl), more preferred a lower alkyl of from one to sixcarbon atoms (C₁₋₆-alkyl), including pentyl, isopentyl, neopentyl,tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkylrepresents a C₁₋₄-alkyl group, including butyl, isobutyl, secondarybutyl, and tertiary butyl. In a most preferred embodiment alkylrepresents a C₁₋₃-alkyl group, which may in particular be methyl, ethyl,propyl or isopropyl.

[0110] In the context of this invention a cycloalkyl group designates acyclic alkyl group, preferably containing of from three to seven carbonatoms (C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl.

[0111] In the context of this invention an alkenyl group designates acarbon chain containing one or more double bonds, including di-enes,tri-enes and poly-enes. In a preferred embodiment the alkenyl group ofthe invention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1,2- or 2,3-propenyl; or1,2-, 2,3-, or 3,4-butenyl.

[0112] In the context of this invention an alkynyl group designates acarbon chain containing one or more triple bonds, including di-ynes,tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group ofthe invention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl, 1,2- or 2,3-propynyl, 1,2-,2,3- or 3,4-butynyl.

[0113] In the context of this invention an alkoxy group designates an“alkyl-O—” group, wherein alkyl is as defined above.

[0114] In the context of this invention an amino group may be a primary(—NH₂), secondary (—NH-alkyl), or tertiary (—N(alkyl)₂) amino group,i.e. it may be substituted once or twice with an alkyl group as definedabove.

[0115] In the context of this invention a mono- or polycyclic aryl groupdesignates a monocyclic or polycyclic aromatic hydrocarbon group.Examples of preferred aryl groups of the invention are phenyl, biphenyl,naphthyl and anthracenyl.

[0116] In the context of this invention a mono- or poly-heterocyclicgroup is a mono- or polycyclic aromatic group, which holds one or moreheteroatoms in its ring structure. Preferred heterocyclic monocyclicgroups of the invention are 5- and 6 membered heterocyclic monocyclicgroups. Examples of preferred heterocyclic monocyclic groups of theinvention include furanyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl,and thienyl. Examples of preferred heterocyclic polycyclic groups of theinvention include benzimidazolyl, indolyl, isoquinolyl and quinolyl.

[0117] The chemical compounds for use according to the invention havebeen described and may be prepared by methods known in the art.

[0118] Pharmaceutically Acceptable Salts

[0119] The chemical compound for use according to the invention may beprovided in any form suitable for the intended administration. Suitableforms include pharmaceutically (i.e. physiologically) acceptable salts,or pre- or prodrug forms of the chemical compound for use according tothe invention.

[0120] Examples of pharmaceutically acceptable addition salts include,without limitation, the non-toxic inorganic and organic acid additionsalts such as the acetate derived from acetic acid, the aconate derivedfrom aconitic acid, the ascorbate derived from ascorbic acid, thebenzenesulfonate derived from benzensulfonic acid, the benzoate derivedfrom benzoic acid, the cinnamate derived from cinnamic acid, the citratederived from citric acid, the embonate derived from embonic acid, theenantate derived from enanthic acid, the formate derived from formicacid, the fumarate derived from fumaric acid, the glutamate derived fromglutamic acid, the glycolate derived from glycolic acid, thehydrochloride derived from hydrochloric acid, the hydrobromide derivedfrom hydrobromic acid, the lactate derived from lactic acid, the maleatederived from maleic acid, the malonate derived from malonic acid, themandelate derived from mandelic acid, the methanesulfonate derived frommethane sulphonic acid, the naphthalene-2-sulphonate derived fromnaphtalene-2-sulphonic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the phthalate derived from phthalic acid, thesalicylate derived from salicylic acid, the sorbate derived from sorbicacid, the stearate derived from stearic acid, the succinate derived fromsuccinic acid, the sulphate derived from sulphuric acid, the tartratederived from tartaric acid, the toluene-p-sulphonate derived fromp-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

[0121] Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound for useaccording to the invention and its pharmaceutically acceptable acidaddition salt.

[0122] Metal salts of a chemical compound for use according to theinvention includes alkali metal salts, such as the sodium salt, of achemical compound for use according to the invention containing acarboxy group.

[0123] In the context of this invention the “onium salts” ofN-containing compounds are also contemplated as pharmaceuticallyacceptable salts. Preferred “onium salts” include the alkyl-onium salts,the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

[0124] The chemical compound for use according to the invention may beprovided in dissoluble or indissoluble forms together with apharmaceutically acceptable solvents such as water, ethanol, and thelike. Dissoluble forms may also include hydrated forms such as themonohydrate, the dihydrate, the hemihydrate, the trihydrate, thetetrahydrate, and the like. In general, the dissoluble forms areconsidered equivalent to indissoluble forms for the purposes of thisinvention.

[0125] Steric Isomers

[0126] The chemical compounds of the present invention may exist in (+)and (−) forms as well as in racemic forms. The racemates of theseisomers and the individual isomers themselves are within the scope ofthe present invention.

[0127] Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l- (tartrates, mandelates,or camphorsulphonate) salts for example.

[0128] The chemical compounds of the present invention may also beresolved by the formation of diastereomeric amides by reaction of thechemical compounds of the present invention with an optically activeactivated carboxylic acid such as that derived from (+) or (−)phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid or bythe formation of diastereomeric carbamates by reaction of the chemicalcompound of the present invention with an optically active chloroformateor the like.

[0129] Additional methods for the resolving the optical isomers areknown in the art. Such methods include those described by Jaques J,Collet A, & Wilen S in “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, New York (1981).

[0130] Moreover, some of the chemical compounds for use according to theinvention being oximes, may thus exist in two forms, syn- and anti-form(Z- and E-form), depending on the arrangement of the substituents aroundthe —C═N— double bond. A chemical compound of the present invention maythus be the syn- or the anti-form (Z- and E-form), or it may be amixture hereof.

[0131] Biological Activity

[0132] As described above, the IK_(Ca) inhibitory compounds for useaccording to the invention are particularly useful as immune modulatingagents, i.e. agents capable of regulating the immune system. Moreparticularly, the IK_(Ca) inhibitory compounds of the present inventionmay be used for reducing or inhibiting undesired immune-regulatoryactions.

[0133] In a preferred embodiment, the invention relates to the use of anIK_(Ca) inhibitory compound for the treatment or alleviation of adiseases, disorders or condition related to immune dysfunction, or inorder to obtain immune suppression in an individual in need herefore.

[0134] In a more preferred embodiment, the invention relates to the useof an IK_(Ca) inhibitory compound of the invention in a combinationtherapy with known immune-suppressants for the treatment or alleviationof a diseases, disorders or condition related to immune dysfunction, orfor obtaining immune suppression. Preferred immune-suppressants tocombine with the compounds of the invention include Amphotericin,Busulphan, Co-trimoxazole, Chlorambucil, colony stimulating factors,corticosteroids, Cyclophosphamide, Fluconazole, folinic acid,Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins,Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus(FK506), Thalidomide, Zolimomab aritox, and the calcineurin inhibitors(protein phosphatase 2B inhibitors), in particular Cyclosporin.

[0135] Conditions which may benefit from this treatment include, but arenot limited to diseases, disorders or conditions such as auto-immunediseases, e.g. Addison's disease, alopecia areata, Ankylosingspondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia(anemia perniciosa), aphthae, aphthous stomatitis, arthritis,arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis,aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immunehemolysis, Bechet's disease, Boeck's disease, inflammatory boweldisease, Burkitt's lymphoma, Chron's disease, chorioiditis, colitisulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis,dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes,idiopathic diabetes insipidus, insulin-dependent diabetes mellisis,auto-immune demyelinating diseases, Dupuytren's contracture,encephalomyelitis, encephalomyelitis allergica, endophthalmiaphacoanaphylactica, enteritis allergica, autoimmune enteropathysyndrome, erythema nodosum leprosum, idiopathic facial paralysis,chronic fatigue syndrome, febris rheumatica, glomerulo nephritis,Goodpasture's syndrome, Graves' disease, Hamman-Rich's disease,Hashimoto's disease, Hashimoto's thyroiditis, sudden hearing loss,sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupuserythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum,mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primaryidiopathic myxedema, nephrosis, ophthalmia symphatica, orchitisgranulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,polyarteritis nodosa, polyarthritis chronica primaria polymyositis,polyradiculitis acuta, psoreasis, purpura, pyoderma gangrenosum,Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxicsclerosis, progressive systemic sclerosis, scleritis, sclerodermia,multiple sclerosis, sclerosis disseminate, acquired spenic atrophy,infertility due to antispermatozoan antobodies, thrombocytopenia,idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis,vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseasessuch as Sjorgren's syndrome, virus (AIDS or EBV) associated B celllymphoma, parasitic diseases such as Lesihmania, and immune-suppresseddisease states such as viral infections following allografttransplantations, graft vs. Host syndrome, transplant rejection, orAIDS, cancer, chronic active hepatitis diabetes, toxic chock syndrome,food poisoning, and transplant rejection.

[0136] Accordingly, in further embodiments, the invention relates to achemical compound having IK_(Ca) inhibitory activity for use as amedicament.

[0137] More specifically the invention relates to the use of a chemicalcompound having selective IK_(Ca) inhibitory activity for use in themanufacture of a medicament for the treatment of treatment of diseasesrelated to immune dysfunction. In a preferred embodiment the medicamentis an immune system suppressing medicament (an immune-suppressivum).

[0138] Pharmaceutical Compositions

[0139] In yet another aspect the invention relates to pharmaceuticalcompositions for use in the treatment or alleviation of diseases,disorders or conditions related to immune dysfunction, whichpharmaceutical composition comprises a therapeutically effective amountof a chemical compound having IK_(Ca) inhibitory activity, as identifiedby the method of the invention.

[0140] While a chemical compound for use according to the invention foruse in therapy may be administered in the form of the raw chemicalcompound, it is preferred to introduce the active ingredient, optionallyin the form of a physiologically acceptable salt, in a pharmaceuticalcomposition together with one or more adjuvants, excipients, carriers,buffers, diluents, and/or other customary pharmaceutical auxiliaries.

[0141] In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound for use according to theinvention or a pharmaceutically acceptable salt or derivative thereoftogether with one or more pharmaceutically acceptable carriers thereforand, optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

[0142] The pharmaceutical composition of the invention may beadministered by any convenient route which suite the desired therapy.Preferred routes of administration include oral administration, inparticular in tablet, in capsule, in drage, in powder, or in liquidform, and parenteral administration, in particular cutaneous,subcutaneous, intramuscular, or intravenous injection. Thepharmaceutical composition may be prepared by the skilled person usingstandard and conventional techniques appropriate to the desiredformulation. When desired, compositions adapted to give sustainedrelease of the active ingredient may be employed.

[0143] The actual dosage depend on the nature and severity of thedisease being treated, and is within the discretion of the physician,and may be varied by titration of the dosage to the particularcircumstances of this invention to produce the desired therapeuticeffect. However, it is presently contemplated that pharmaceuticalcompositions containing of from about 0.1 to about 500 mg of activeingredient per individual dose, preferably of from about 1 to about 100mg, most preferred of from about 1 to about 10 mg, are suitable fortherapeutic treatments.

[0144] Further details on techniques for formulation and administrationmay be found in the latest edition of Remington's PharmaceuticalSciences (Maack Publishing Co., Easton, Pa.).

[0145] The actual dosage depend on the nature and severity of thedisease being treated, and is within the discretion of the physician,and may be varied by titration of the dosage to the particularcircumstances of this invention to produce the desired therapeuticeffect. However, it is presently contemplated that pharmaceuticalcompositions containing of from about 0.1 to about 500 mg of activeingredient per individual dose, preferably of from about 1 to about 100mg, most preferred of from about 1 to about 10 mg, are suitable fortherapeutic treatments.

[0146] The active ingredient may be administered in one or several dosesper day. A satisfactory result can, in certain instances, be obtained ata dosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit ofthe dosage range is presently considered to be about 10 mg/kg i.v. and100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

[0147] Methods of Therapy

[0148] Viewed from another aspect, the invention provides a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disease,disorder or condition is responsive to IK_(Ca) inhibitory compounds.

[0149] Therefore, in a preferred embodiment, the invention provides amethod of treatment or alleviation of diseases, disorders or conditionsrelating to immune dysfunction in a living body, said method comprisingadministering to said living body an effective amount of a chemicalcompound having IK_(Ca) inhibitory activity.

[0150] In a more preferred embodiment, the disease, disorder orcondition relating to immune dysfunction is an auto-immune disease, e.g.Addison's disease, alopecia areata, Ankylosing spondylitis, haemolyticanemia (anemia haemolytica), pernicious anemia (anemia perniciosa),aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders,osteoarthritis, rheumatoid arthritis, aspermiogenese, asthma bronchiale,auto-immune asthma, auto-immune hemolysis, Bechet's disease, Boeck'sdisease, inflammatory bowel disease, Burkitt's lymphoma, Chron'sdisease, chorioiditis, colitis ulcerosa, Coeliac disease,cryoglobulinemia, dermatitis herpetiformis, dermatomyositis,insulin-dependent type I diabetes, juvenile diabetes, idiopathicdiabetes insipidus, insulin-dependent diabetes mellisis, auto-immunedemyelinating diseases, Dupuytren's contracture, encephalomyelitis,encephalomyelitis allergica, endophthalmia phacoanaphylactica, enteritisallergica, autoimmune enteropathy syndrome, erythema nodosum leprosum,idiopathic facial paralysis, chronic fatigue syndrome, febrisrheumatica, glomerulo nephritis, Goodpasture's syndrome, Graves'disease, Hamman-Rich's disease, Hashimoto's disease, Hashimoto'sthyroiditis, sudden hearing loss, sensoneural hearing loss, hepatitischronica, Hodgkin's disease, haemoglobinuria paroxysmatica,hypogonadism, ileitis regionalis, iritis, leucopenia, leucemia, lupuserythematosus disseminatus, systemic lupus erythematosus, cutaneouslupus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa,myasthenia gravis, traverse myelitis, primary idiopathic myxedema,nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis,pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritischronica primaria, polymyositis, polyradiculitis acuta, psoreasis,purpura, pyoderma gangrenosum, Quervain's thyreoiditis, Reiter'ssyndrome, sarcoidosis, ataxic sclerosis, progressive systemic sclerosis,scleritis, sclerodermia, multiple sclerosis, sclerosis disseminate,acquired spenic atrophy, infertility due to antispermatozoan antobodies,thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma, acuteanterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virusassociated diseases such as Sjorgren's syndrome, virus (AIDS or EBV)associated B cell lymphoma, parasitic diseases such as Lesihmania, andimmune-suppressed disease states such as viral infections followingallograft transplantations, graft vs. Host syndrome, transplantrejection, or AIDS, cancer, chronic active hepatitis diabetes, toxicchock syndrome, food poisoning, or transplant rejection.

[0151] In another preferred embodiment, the method of the inventioncomprises simultaneous administration of the chemical compound havingselective IK_(Ca) inhibitory activity and a pharmaceutically effectiveamount of a conventional immune suppressing agent.

[0152] In a more preferred embodiment the immune-suppressing agent isAmphotericin, Busulphan, Co-trimoxazole, Chlorambucil, colonystimulating factors, corticosteroids, Cyclophosphamide, Fluconazole,folinic acid, Ganciclovir, antilymphocyte immunoglobulins, normalimmunoglobulins, Methotrexate, Methylprednisolone, Octreotide,Oxpentifylline, Tacrolimus (FK506), Thalidomide, Zolimomab aritox, orthe calcineurin inhibitors (protein phosphatase 2B inhibitors), inparticular Cyclosporin.

[0153] It is at present contemplated that suitable dosage ranges are 0.1to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

BRIEF DESCRIPTION OF THE DRAWINGS

[0154] The present invention is further illustrated by reference to theaccompanying drawing, in which:

[0155]FIG. 1 shows the effect of a compound of the invention(Clotrimazole) on Cyclosporin A mediated inhibition of T cellproliferation (PPD-induced T cell proliferation) on a relative scale offrom 0,00 to 1,25, carried out as described in Example 2 [with andwithout (Control) Clotrimazole, 10 μM; Combined with Cyclosporin A, inconcentrations of 0, 2.5, 5, 10 and 25 nM, respectively].

EXAMPLES

[0156] The invention is further illustrated with reference to thefollowing examples which are not intended to be in any way limiting tothe scope of the invention as claimed.

Example 1

[0157] Inhibition of T Cell Proliferation

[0158] The chemical compounds used according to the invention preventimmunological proliferation by selective inhibition of theCa²⁺-activated K-channels in T- and B-lymphocytes. This effect may beverified using various proliferation assays. In this experiment theproliferative assay described by Ødum et al. [Ødum N, Kanner S B,Ledbetter J A, & Svejgaard A; J. Immunol. 1993 150 (12) 5289-5298] wasused.

[0159] The chemical compounds representative for the invention tested inthis experiment are (4-chlorophenyl-diphenyl)-carbinol (A);ethyl-2-phenyl-2-(1-piperidyl)-phenylacetate (B); and1,1,1-triphenylacetone (C); all compounds commercially available fromSigma-Aldrich, Denmark.

[0160] Assays were performed in culture medium (RPMI 1640; availablefrom Gibco, Grand Island, N.Y.) supplemented with 10% pooled humanserum, 2 mM L-glutamine, 100 μg/ml penicillin, and 100 μg/mlstreptomycin (available from Novo Nordisk, Copenhagen, Denmark) in96-well round bottom tissue culture plates (available from Nunc,Roskilde, Denmark) with a final volume of 200 μl.

[0161] T cells were pre-incubated for three hours with the testcompounds before addition of antigen (PPD; Purified protein derivative,available from Statens Serum Institut, Denmark; 100 μg/ml). T cells werecultured at 5×10⁴ cells/well for 144 hours. Twelve hours before harvest,[³H]thymidine (1×Ci/well) was added. The cells were harvested onto glassfibre filters, and the [³H]thymidine incorporation was measured in ascintillation counter. The results were expressed as mean counts perminute (cpm) from triplicate cultures.

[0162] The results are presented in Table 1, below. TABLE 1 Inhibitionof T Cell Proliferation T Cell Proliferation (cpm × 10⁻³) Test MediumAntigen, PPD Compound Solvent Solvent 2.5 μM 10 μM 25 μM A 0.2 26.1 21.519.8 18.1 B 0.2 26.1 22.5 20 19 C 0.2 26.1 25.5 18 19

[0163] These results show that the number of T cells decreases in thepresence of increasing concentrations of the chemical compound for useaccording to the invention, and support the fact that the chemicalcompounds for use according to the invention inhibit the antigen inducedT cell proliferation and thus are useful for the reduction or inhibitionof undesired immune-regulatory actions.

Example 2

[0164] Combination Treatment

[0165] In this example, the effect of a compound of this invention(Clotrimazole) on Cyclosporin A mediated inhibition of T cellproliferation is determined.

[0166] T cells were stimulated with antigen in the presence ofCyclosporin A, or Cyclosporin A and Clotrimazole, respectively.

[0167] The proliferation assay described in Example 1, was used.

[0168] Cells were incubated for 5 days in culture medium with PPD in thepresence of Cyclosporin A, or Cyclosporin A and Clotrimazole,respectively. Clotrimazole (10 μM) was added 30 minutes prior to theaddition of antigen. [³H]thymidine (1 mM Ci) incorporation was thenmeasured in triplicate wells. The bars shown in FIG. 1 represent 3independent experiments ±S.E. (p≦0.05 vs. control). Eleven otherexperiments using Candida albicans antigen, tetanus toxin, Con A or PHAas the antigen/mitogen challenge gave similar results.

[0169] T cell proliferation was assayed 6 days after stimulation using3H-thymidine incorporation. The Cyclosporin A mediated inhibition of Tcell proliferation is shifted leftwards by 10 μM Clotrimazole, from a50% inhibition of proliferation at approximately 25 nM Cyclosporin A tohalf-maximal inhibition at 2.5 nM Cyclosporin A.

[0170] This suggests that the antigen-induced T cell proliferation ishighly sensitive to both IK channel block and inhibition of calcineurin,and data indicate that the IK channel is highly important for normal Tcell proliferation and suggest that IK channels are attractive targetsfor immune suppression.

1. Use of a chemical compound having selective IK_(Ca) modulatoryactivity for the manufacture of a medicament for the treatment,prevention or alleviation of a disease or a disorder or a condition of amammal, including a human, which disease, disorder or condition relatesto immune dysfunction.
 2. The use according to claim 1, wherein thechemical compound is a triaryl methane derivative represented by thegeneral Formula I

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5 or 6; X is absent, or represent a groupof the formula —(CH₂)_(n)—, of the formula —(CH₂)_(n)—Z— (in eitherdirection), of the formula —(CH₂)_(n)—CH═N— (in either direction), theformula —(CH₂)_(n)—Z—(CH₂)_(m)—, or of the formula—(CH₂)_(n)—CH═N—(CH₂)_(m)— (in either direction), or a group of theformula —R′″C(O)N—; in which formulas n and m, independently of eachanother, represent 0, 1, 2, 3 or 4; and Z represents O, S, or NR′″,wherein R′″ represents hydrogen or alkyl; Y represents a carbon atom(C), a nitrogen atom (N), or a phosphor atom (P), a silicium atom (Si),or a germanium atom (Ge); Ar¹, Ar² and Ar³, independently of eachanother, represents a partially or completely saturated mono- orpolycyclic aryl group, or a mono- or poly-heterocyclic group, whichmono- or polycyclic groups may optionally be substituted one or moretimes with substituents selected from the group consisting of halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR″, —SR″, —R′OR″, —R′SR″, —C(O)R″,—C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″),—C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂,—C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂,—CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″; R representshydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro or cyano, or a group of the formula —OR′, —SR′,—R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′,—C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′),—CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂,—CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or—CH₂SR′; or a partially or completely saturated mono- or polycyclic arylgroup, or a mono- or poly-heterocyclic group, which mono- or polycyclicgroups may optionally be substituted one or more times with substituentsselected from the group consisting of hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, or —SR′; and R′ and R″,independently of each another, represents hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, or alkoxy.
 3. The use according to claim 2, whereinthe partially or completely saturated mono- or polycyclic aryl group isselected from the group consisting phenyl, biphenyl, naphthyl, orcyclopenta-2,4-diene-1-ylidene; and the mono- or poly-heterocyclic groupis A 5- and 6 membered heterocyclic monocyclic group selected from thegroup consisting of furanyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,thiadiazolyl, thiazolyl, thienyl, and butyrolactonyl, in particularγ-butyrolactonyl.
 4. The use according to claim 2, wherein the chemicalcompound is a triaryl methane derivative represented by the generalFormula II

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5 or 6; Ar¹ represents a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; R represents hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′), —C(S)NR″(OR′),—C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂, —C(S)NR′₂,—CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂, —CH[C(O)SR′]₂,—CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially or completelysaturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; which triaryl methane derivative may further besubstituted one or more times with a substituent X selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR″, —SR″, —R′OR″, —R′S R″, —C(O)R″, —C(S)R″, —C(O)OR″,—C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″),—C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂,—CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂,—CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″; and R′ and R″, independently of eachanother, represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, oralkoxy.
 5. The use according to claim 4, wherein the partially orcompletely saturated mono- or polycyclic aryl group is selected from thegroup consisting phenyl, biphenyl, naphthyl, orcyclopenta-2,4-diene-1-ylidene; and the mono- or poly-heterocyclic groupis A 5- and 6 membered heterocyclic monocyclic group selected from thegroup consisting of furanyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,thiadiazolyl, thiazolyl, thienyl, and butyrolactonyl, in particularγ-butyrolactonyl.
 6. The use according to claim 2, wherein the triarylmethane derivative is represented by the general Formula III

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R¹, R², R³ and R⁴, independently of each another,represents hydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.
 7. The useaccording to claim 6, wherein the partially or completely saturatedmono- or polycyclic aryl group is selected from the group consistingphenyl, biphenyl, naphthyl, or cyclopenta-2,4-diene-1-ylidene; and themono- or poly-heterocyclic group is A 5- and 6 membered heterocyclicmonocyclic group selected from the group consisting of furanyl,imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.8. The use according to claim 2, wherein the triaryl methane derivativeis represented by the general Formula IV

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R¹, R² and R³, independently of each another,represents hydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.
 9. The useaccording to claim 8, wherein the partially or completely saturatedmono- or polycyclic aryl group is selected from the group consistingphenyl, biphenyl, naphthyl, or cyclopenta-2,4-diene-1-ylidene; and themono- or poly-heterocyclic group is A 5- and 6 membered heterocyclicmonocyclic group selected from the group consisting of furanyl,imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.10. The use according to claim 2, wherein the triaryl methane derivativeis represented by the general Formula V

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; Ar¹ represents a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR″, —SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″,—C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″),—C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂,—CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂,—CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R″]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R¹ and R², independently of each another,represents hydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.
 11. The useaccording to claim 10, wherein the partially or completely saturatedmono- or polycyclic aryl group is selected from the group consistingphenyl, biphenyl, naphthyl, or cyclopenta-2,4-diene-1-ylidene; and themono- or poly-heterocyclic group is A 5- and 6 membered heterocyclicmonocyclic group selected from the group consisting of furanyl,imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.12. The use according to claim 2, wherein the triaryl methane derivativeis represented by the general Formula VI

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R¹, R², R³ and R⁴, independently of each another,represents hydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R′, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.
 13. The useaccording to claim 12, wherein the partially or completely saturatedmono- or polycyclic aryl group is selected from the group consistingphenyl, biphenyl, naphthyl, or cyclopenta-2,4-diene-1-ylidene; and themono- or poly-heterocyclic group is A 5- and 6 membered heterocyclicmonocyclic group selected from the group consisting of furanyl,imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.14. The use according to claim 2, wherein the triaryl methane derivativeis represented by the general Formula VII

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[CO(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R¹, R² and R³, independently of each another,represents hydrogen, halogen, trihalogenmethyl, alkyl, cycloalkyl,alkenyl, alkynyl, amino, nitro or cyano, or a group of the formula —OR″,—SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″,—C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″), —C(O)NR′(SR″), —C(S)NR′(SR″),—CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂, —CH[C(O)R″]₂, —CH[C(S)R″]₂,—CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂, —CH[C(S)SR″]₂, —CH₂OR″, or—CH₂SR″; and R′ and R″, independently of each another, representshydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy.
 15. The useaccording to claim 14, wherein the partially or completely saturatedmono- or polycyclic aryl group is selected from the group consistingphenyl, biphenyl, naphthyl, or cyclopenta-2,4-diene-1-ylidene; and themono- or poly-heterocyclic group is A 5- and 6 membered heterocyclicmonocyclic group selected from the group consisting of furanyl,imidazolyl, isoimidazolyl, 2-isoimidazolyl, isothiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, and butyrolactonyl, in particular γ-butyrolactonyl.16. The use according to claim 2, wherein the triaryl methane derivativeis represented by the general Formula VIII

and a pharmaceutically acceptable salt or an oxide or a hydrate thereof,wherein, n is 0, 1, 2, 3, 4, 5, or 6; Ar¹ represents a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpoly-heterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR″, —SR″, —R′OR″, —R′SR″, —C(O)R″, —C(S)R″, —C(O)OR″,—C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)NR′(OR″), —C(S)NR′(OR″),—C(O)NR′(SR″), —C(S)NR′(SR″), —CH(CN)₂, —C(O)NR″₂, —C(S)NR″₂,—CH[C(O)R″]₂, —CH[C(S)R″]₂, —CH[C(O)OR″]₂, —CH[C(S)OR″]₂, —CH[C(O)SR″]₂,—CH[C(S)SR″]₂, —CH₂OR″, or —CH₂SR″; R represents hydrogen, halogen,trihalogenmethyl, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro orcyano, or a group of the formula —OR′, —SR′, —R″OR′, —R″SR′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, —C(O)NR″(OR′),—C(S)NR″(OR′), —C(O)NR″(SR′), —C(S)NR″(SR′), —CH(CN)₂, —C(O)NR′₂,—C(S)NR′₂, —CH[C(O)R′]₂, —CH[C(S)R′]₂, —CH[C(O)OR′]₂, —CH[C(S)OR′]₂,—CH[C(O)SR′]₂, —CH[C(S)SR′]₂, —CH₂OR′, or —CH₂SR′; or a partially orcompletely saturated mono- or polycyclic aryl group, or a mono- orpolyheterocyclic group, which mono- or polycyclic groups may optionallybe substituted one or more times with substituents selected from thegroup consisting of hydrogen, halogen, trihalogenmethyl, alkyl,cycloalkyl, alkenyl, alkynyl, amino, nitro or cyano, or a group of theformula —OR′, or —SR′; R′ and R″, independently of each another,represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy. 17.The use according to claim 16, wherein the partially or completelysaturated mono- or polycyclic aryl group is selected from the groupconsisting phenyl, biphenyl, naphthyl, orcyclopenta-2,4-diene-1-ylidene; and the mono- or poly-heterocyclic groupis A 5- and 6 membered heterocyclic monocyclic group selected from thegroup consisting of furanyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl,isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, piperidyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,thiadiazolyl, thiazolyl, thienyl, and butyrolactonyl, in particularγ-butyrolactonyl.
 18. The use according to claim 2, wherein the compoundis (4-chlorophenyl-diphenyl)-carbinol; Ethyl2-phenyl-2-(1-piperidyl)-phenylacetate; or 1,1,1-triphenylacetone; or apharmaceutically acceptable salt or an oxide or a hydrate hereof. 19.The use according to any of claims 1-18, wherein the disease, disorderor condition relating to immune dysfunction is an auto-immune disease,e.g. Addison's disease, alopecia areata, Ankylosing spondylitis,haemolytic anemia (anemia haemolytica), pernicious anemia (anemiaperniciosa), aphthae, aphthous stomatitis, arthritis, arterioscleroticdisorders, osteoarthritis, rheumatoid arthritis, aspermiogenese, asthmabronchiale, auto-immune asthma, auto-immune hemolysis, Bechet's disease,Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma, Chron'sdisease, chorioiditis, colitis ulcerosa, Coeliac disease,cryoglobulinemia, dermatitis herpetiformis, dermatomyositis,insulin-dependent type I diabetes, juvenile diabetes, idiopathicdiabetes insipidus, insulin-dependent diabetes mellisis, auto-immunedemyelinating diseases, Dupuytren's contracture, encephalomyelitis,encephalomyelitis allergica, endophthalmia phacoanaphylactica, enteritisallergica, autoimmune enteropathy syndrome, erythema nodosum leprosum,idiopathic facial paralysis, chronic fatigue syndrome, febrisrheumatica, glomerulo nephritis, Goodpasture's syndrome, Graves'disease, Hamman—Rich's disease, Hashimoto's disease, Hashimoto'sthyroiditis, sudden hearing loss, sensoneural hearing loss, hepatitischronica, Hodgkin's disease, haemoglobinuria paroxysmatica,hypogonadism, ileitis regionalis, iritis, leucopenia, leucemia, lupuserythematosus disseminatus, systemic lupus erythematosus, cutaneouslupus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa,myasthenia gravis, traverse myelitis, primary idiopathic myxedema,nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis,pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritischronica primaria, polymyositis, polyradiculitis acuta, psoreasis,purpura, pyoderma gangrenosum, Quervain's thyreoiditis, Reiter'ssyndrome, sarcoidosis, ataxic sclerosis, progressive systemic sclerosis,scleritis, sclerodermia, multiple sclerosis, sclerosis disseminata,acquired spenic atrophy, infertility due to antispermatozoan antobodies,thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma, acuteanterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virusassociated diseases such as Sjorgren's syndrome, virus (AIDS or EBV)associated B cell lymphoma, parasitic diseases such as Lesihmania, andimmune-suppressed disease states such as viral infections followingallograft transplantations, graft vs. Host syndrome, transplantrejection, or AIDS, cancer, chronic active hepatitis diabetes, toxicchock syndrome, food poisoning, or transplant rejection.
 20. The useaccording to claims 1-19, for the manufacture of a medicament whichmedicament further comprises a pharmaceutically effective amount of aconventional immune suppressing agent.
 21. The use according to claim20, wherein the immune-suppressing agent is Amphotericin, Busulphan,Co-trimoxazole, Chlorambucil, colony stimulating factors,corticosteroids, Cyclophosphamide, Fluconazole, folinic acid,Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins,Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus(FK506), Thalidomide, Zolimomab aritox, or the calcineurin inhibitors(protein phosphatase 2B inhibitors), in particular Cyclosporin.
 22. Amethod for of treatment, prevention or alleviation of a disease or adisorder or a condition related to immune dysfunction, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a chemical compound havingselective IK_(Ca) inhibitory activity.
 23. The method according to claim22, wherein the disease, disorder or condition relating to immunedysfunction is an auto-immune disease, e.g. Addison's disease, alopeciaareata, Ankylosing spondylitis, haemolytic anemia (anemia haemolytica),pernicious anemia (anemia perniciosa), aphthae, aphthous stomatitis,arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoidarthritis, aspermiogenese, asthma bronchiale, auto-immune asthma,auto-immune hemolysis, Bechet's disease, Boeck's disease, inflammatorybowel disease, Burkitt's lymphoma, Chron's disease, chorioiditis,colitis ulcerosa, Coeliac disease, cryoglobulinemia, dermatitisherpetiformis, dermatomyositis, insulin-dependent type I diabetes,juvenile diabetes, idiopathic diabetes insipidus, insulin-dependentdiabetes mellisis, auto-immune demyelinating diseases, Dupuytren'scontracture, encephalomyelitis, encephalomyelitis allergica,endophthalmia phacoanaphylactica, enteritis allergica, autoimmuneenteropathy syndrome, erythema nodosum leprosum, idiopathic facialparalysis, chronic fatigue syndrome, febris rheumatica, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Hamman-Rich'sdisease, Hashimoto's disease, Hashimoto's thyroiditis, sudden hearingloss, sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupuserythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum,mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primaryidiopathic myxedema, nephrosis, ophthalmia symphatica, orchitisgranulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,polyarteritis nodosa, polyarthritis chronica primaria, polymyositis,polyradiculitis acuta, psoreasis, purpura, pyoderma gangrenosum,Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxicsclerosis, progressive systemic sclerosis, scleritis, sclerodermia,multiple sclerosis, sclerosis disseminata, acquired spenic atrophy,infertility due to antispermatozoan antobodies, thrombocytopenia,idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis,vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseasessuch as Sjorgren's syndrome, virus (AIDS or EBV) associated B celllymphoma, parasitic diseases such as Lesihmania, and immune-suppresseddisease states such as viral infections following allografttransplantations, graft vs. Host syndrome, transplant rejection, orAIDS, cancer, chronic active hepatitis diabetes, toxic chock syndrome,food poisoning, or transplant rejection.
 24. The method according toeither of claims 22-23, which method comprises simultaneousadministration of the chemical compound having selective IK_(Ca)inhibitory activity and a pharmaceutically effective amount of aconventional immune suppressing agent.
 25. The method according to claim24, wherein the immune-suppressing agent is Amphotericin, Busulphan,Co-trimoxazole, Chlorambucil, colony stimulating factors,corticosteroids, Cyclophosphamide, Fluconazole, folinic acid,Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins,Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus(FK506), Thalidomide, Zolimomab aritox, or the calcineurin inhibitors(protein phosphatase 2B inhibitors), in particular Cyclosporin.